Fertility Control

Question 1

Female Reproductive Endocrinology - Fertility Control

• GnRH released from the …
• Works on … pituitary to release LH and FSH
  
  • These stimulate the ovary to make the egg and also make oestrogen and progesterone
    
    • These hormones work in a … feedback mechanism on GnRH and pituitary to … LH and FSH production
• Hormonal contraception with high levels of oestrogen and/or progesterone will have the same … feedback effect - … production of LH and FSH - … stimulation of developing follicles and make implantation … likely

Answer 1

• GnRH released from the hypothalamus
• Works on anterior pituitary to release LH and FSH
  
  • These stimulate the ovary to make the egg and also make oestrogen and progesterone
    
    • These hormones work in a negative feedback mechanism on GnRH and pituitary to reduce LH and FSH production
• Hormonal contraception with high levels of oestrogen and/or progesterone then this will have the same negative feedback effect - decreasing production of LH and FSH - decreasing stimulation of developing follicles and make implantation less likely

Question 2

Combined Hormonal Contraceptives (CHC)

• Available as … (COC), … patches (CTP), and vaginal … (CVR).
• Highly …-dependant methods where the failure rate if used perfectly (i.e. correctly and consistently) is less than …%.
• Certain factors such as the person’s …, … including diarrhoea and vomiting (COC only), and drug … (enzyme inducing drugs) may contribute to contraceptive failure.
• Prescriptions of up to … months’ supply for CHC initiation or continuation may be appropriate to avoid unwanted discontinuation and increased risk of pregnancy.
• Should not be continued beyond … years of age as safer alternatives exist.

Answer 2

• Available as tablets (COC), transdermal patches (CTP), and vaginal rings (CVR).
• Highly user-dependant methods where the failure rate if used perfectly (i.e. correctly and consistently) is less than 1%.
• Certain factors such as the person’s weight, malabsorption including diarrhoea and vomiting (COC only), and drug interactions (enzyme inducing drugs) may contribute to contraceptive failure.
• Prescriptions of up to 12 months’ supply for CHC initiation or continuation may be appropriate to avoid unwanted discontinuation and increased risk of pregnancy.
• Should not be continued beyond 50 years of age as safer alternatives exist.

Question 3

Benefits of Combined Hormonal Contraceptives

• Reduced risk of …, … and … cancer;
• … bleeding patterns
• Reduced dys… and men…;
• Management of symptoms of p…, e… and … syndrome;
• Improvement of …;
• Reduced … symptoms;
• Maintaining … … density in peri-menopausal females under the age of … years.

Answer 3

• Reduced risk of ovarian, endometrial and colorectal cancer;
• Predictable bleeding patterns
• Reduced dysmenorrhoea and menorrhagia;
• Management of symptoms of polycystic ovary syndrome (PCOS), endometriosis and premenstrual syndrome;
• Improvement of acne;
• Reduced menopausal symptoms;
• Maintaining bone mineral density in peri-menopausal females under the age of 50 years.

Question 4

Risks with Combined Hormonal Contraceptives

• … cancer and … cancer associated with current or recent use of CHC issmall, but is greater than that with progestogen-only or non-hormonal contraception.
• Venous and arterial …
  
  • CHC is associated with a …-…-fold increase in VTE risk compared with non-use of CHC.
    
    • Absolute risk of VTE during use of CHC is estimated by the European Medicines Agency to be between 5 and 12 per 10 000 women per year of use compared to 2 per 10 000 non-CHC users per year.
    • NB VTE risk is lower during CHC use than during … and the … period.
    • By reducing rates of … pregnancy, CHC use lowers the overall rate of VTE in the population in comparison to populations without access to effective contraception.
• VTE events that do occur during use of CHC, approximately …% are fatal
• … (LNG), … (NET) and Nor… COC are associated with a lower risk of venous thromboembolic events than COC containing newer progestogens, the combined transdermal patch and the combined vaginal ring.
• COC containing higher EE (…) doses may be associated with greater risk of arterial thrombotic events than lower EE doses.

Answer 4

• Breast cancer and cervical cancer associated with current or recent use of CHC is
• small, but is greater than that with progestogen-only or non-hormonal contraception.
• Venous and arterial thromboembolism
  
  • CHC is associated with a 3- to 3.5-fold increase in VTE risk compared with non-use of CHC.
    
    • Absolute risk of VTE during use of CHC is estimated by the European Medicines Agency to be between 5 and 12 per 10 000 women per year of use compared to 2 per 10 000 non-CHC users per year.
    • NB VTE risk is lower during CHC use than during pregnancy and the postpartum period.
    • By reducing rates of unplanned pregnancy, CHC use lowers the overall rate of VTE in the population in comparison to populations without access to effective contraception.
• VTE events that do occur during use of CHC, approximately 1% are fatal
• Levonorgestrel (LNG), norethisterone (NET) and norgestimate COC are associated with a lower risk of venous thromboembolic events than COC containing newer progestogens, the combined transdermal patch and the combined vaginal ring.
• COC containing higher EE (ethinylestradiol) doses may be associated with greater risk of arterial thrombotic events than lower EE doses.

Question 5

What does this table show?

Answer 5

Risks with combined hormonal contraceptives

Question 6

Options for how to use Combined Hormonal Contraception

• Standard use: How many days for pill/ how many rings/patch and what break?
• Shortened hormone-free interval: How many days for pill/ how many rings/patch and what break?
• Extended use: How many days for pill/ how many rings/patch and what break?
• Flexible extended use: How many days for pill/ how many rings/patch and what break?
• Continuous use: How many days for pill/ how many rings/patch and what break?

Answer 6

• Standard use: 21 days (21 active pills or 1 ring, or 3 patches) break of 7 days
• Tailored Use
• Shortened hormone-free interval: 21 days (21 active pills or 1 ring, or 3 patches) break of 4 days
• Extended use: 9 weeks ( 3 x 21 active pills or 3 rings, or 9 patches used consecutively) break = 4 or 7 days
• Flexible extended use: Continuous use (>21 days) of active pills, patches or rings until breakthrough bleeding occurs for 3-4 days. Break = 4 days
• Continuous use: Continuous use of active pills, patches or rings - no break

Question 7

Oral progestogen-only contraceptives​

• Alter … … to prevent … and may inhibit … in some women;
• … desogestrel-only preparations consistently inhibit ovulation and this is their … mechanism of action.
• Progestogen-only contraceptives offer a suitable alternative to combined hormonal contraceptives when oestrogens are …

Answer 7

• Alter cervical mucus to prevent sperm penetration and may inhibit ovulation in some women;
• Oral desogestrel-only preparations consistently inhibit ovulation and this is their primary mechanism of action.
• Progestogen-only contraceptives offer a suitable alternative to combined hormonal contraceptives when oestrogens are contra- indicated.

Question 8

Parenteral Progestogen-only contraceptives

• Medroxyprogesterone acetate (Depo-Provera®, SAYANA PRESS®) is a …-acting progestogen given by …;
• At least as effective as the … preparations
• … action, it may be used as a short-term or long-term contraceptive for women
• … return of … and … cycles may occur after discontinuation of treatment but there is no evidence of …
• Norethisterone enantate (Noristerat®) is a long-acting progestogen given as an oily injection which provides contraception for …; it is used as short-term interim contraception e.g. before vasectomy becomes effective.
• E…-releasing implant (Nexplanon®) is also available.
  
  • Highly effective long-acting contraceptive, consisting of a single flexible rod that is inserted subdermally into the lower surface of the upper arm and provides contraception for up to … Local reactions such as bruising and itching can occur at the insertion site. The contraceptive effect of etonogestrel is rapidly reversed on removal of the implant.

Answer 8

• Medroxyprogesterone acetate (Depo-Provera®, SAYANA PRESS®) is a long-acting progestogen given by injection;
• At least as effective as the combined oral preparations
• Prolonged action, it may be used as a short-term or long-term contraceptive for women
• Delayed return of fertility and irregular cycles may occur after discontinuation of treatment but there is no evidence of permanent infertility.
• Norethisterone enantate (Noristerat®) is a long-acting progestogen given as an oily injection which provides contraception for 8 weeks; it is used as short-term interim contraception e.g. before vasectomy becomes effective.
• Etonogestrel-releasing implant (Nexplanon®) is also available.
  
  • Highly effective long-acting contraceptive, consisting of a single flexible rod that is inserted subdermally into the lower surface of the upper arm and provides contraception for up to 3 years. Local reactions such as bruising and itching can occur at the insertion site. The contraceptive effect of etonogestrel is rapidly reversed on removal of the implant

Question 9

Intra-uterine progestogen-only device

• Mirena®, Jaydess® and Levosert® release … directly into the uterine cavity.
• Licensed for contraception and some licensed for the treatment of …
  
  • Effects - prevention of endometrial …, thickening of cervical …, and suppression of … in some women (in some cycles), the intra-uterine system itself may contribute slightly to the contraceptive effect.
• Return of … after removal is rapid and appears to be complete.
• Advantages over … intra-uterine devices - improvement in any … and a reduction in blood loss; possible reduced pelvic … disease

Answer 9

• Mirena®, Jaydess® and Levosert® release levonorgestrel directly into the uterine cavity.
• Licensed for contraception and some licensed for the treatment of menorrhagia
• Effects - prevention of endometrial proliferation, thickening of cervical mucus, and suppression of ovulation in some women (in some cycles), the intra-uterine system itself may contribute slightly to the contraceptive effect.
• Return of fertility after removal is rapid and appears to be complete.
• Advantages over copper intra-uterine devices - improvement in any dysmenorrhoea and a reduction in blood loss; possible reduced pelvic inflammatory disease

Question 10

Comparative contraceptive success rates

• Perfect use of CHC - …% failure rate compared to …% typical use
• Perfect use of Progestogen-only injectable - …% failure rate compared to …% typical use
• Progestogen-only implant - …% failure rate
• Which is best in terms of success rates?

Answer 10

• Perfect use of CHC - 0.3% failure rate compared to 9% typical use
• Perfect use of Progestogen-only injectable - 0.2% failure rate compared to 6% typical use
• Progestogen-only implant - 0.05% failure rate
• Progestogen-only implant - best in terms of success rates

Question 11

Emergency Contraception

• Hormonal emergency contraceptives (includes levonorgestrel and ulipristal acetate) should be offered as soon as possible after unprotected intercourse if a … intra-uterine device is not appropriate or is not acceptable to the patient; either drug should be taken as soon as possible after unprotected intercourse to increase ….
  
  • Hormonal emergency contraception administered after … is ineffective.
• Levonorgestrel is effective if taken within … hours (…) of unprotected intercourse and may also be used between … and … hours after unprotected intercourse [unlicensed use], but efficacy decreases with time.
• Ulipristal acetate is effective if taken within … hours (… days) of unprotected intercourse.
• Ulipristal acetate has been demonstrated to be … effective than levonorgestrel for emergency contraception.
• It is possible that a… could reduce the effectiveness of oral emergency contraception, particularly levonorgestrel; if BMI is greater than … g/m2 or body-weight is greater than … kg, it is recommended that either ulipristal acetate or a double dose of levonorgestrel [unlicensed indication] (see Emergency contraception under levonorgestrel) is given. It is unknown which is more effective.
• … should be considered as the first-line hormonal emergency contraceptive for a woman who has had unprotected intercourse 96–120 hours ago (even if she has also had unprotected intercourse within the last 96 hours). It should also be considered first line for a woman who has had unprotected sexual intercourse within the last 5 days if it is likely to have taken place during the 5 days before the estimated day of ovulation.

Answer 11

• Hormonal emergency contraceptives (includes levonorgestrel and ulipristal acetate) should be offered as soon as possible after unprotected intercourse if a copper intra-uterine device is not appropriate or is not acceptable to the patient; either drug should be taken as soon as possible after unprotected intercourse to increase efficacy.
  
  • Hormonal emergency contraception administered after ovulation is ineffective.
• Levonorgestrel is effective if taken within 72 hours (3 days) of unprotected intercourse and may also be used between 72 and 96 hours after unprotected intercourse [unlicensed use], but efficacy decreases with time.
• Ulipristal acetate is effective if taken within 120 hours (5 days) of unprotected intercourse.
• Ulipristal acetate has been demonstrated to be more effective than levonorgestrel for emergency contraception.
• It is possible that a higher body-weight or BMI could reduce the effectiveness of oral emergency contraception, particularly levonorgestrel; if BMI is greater than 26 g/m2 or body-weight is greater than 70 kg, it is recommended that either ulipristal acetate or a double dose of levonorgestrel [unlicensed indication] (see Emergency contraception under levonorgestrel) is given. It is unknown which is more effective.
• Ulipristal acetate should be considered as the first-line hormonal emergency contraceptive for a woman who has had unprotected intercourse 96–120 hours ago (even if she has also had unprotected intercourse within the last 96 hours). It should also be considered first line for a woman who has had unprotected sexual intercourse within the last 5 days if it is likely to have taken place during the 5 days before the estimated day of ovulation.

Question 12

Male Reproductive Endocrinology - Female Control

• GnRH released from hypothalamus
• Stimulates production LH and FSH from pituitary
  
  • LH stimulates production of testosterone in Leydig Cells - negative feedback on GnRH and LH
• Male hormonal contraception - focus on increasing testosterone levels which exploits this loop - reduction of GnRH - decreases FSH and sperm production

Answer 12

• GnRH released from hypothalamus
• Stimulates production LH and FSH from pituitary
  
  • LH stimulates production of testosterone in Leydig Cells - negative feedback on GnRH and LH
• Male hormonal contraception - focus on increasing testosterone levels which exploits this loop - reduction of GnRH - decreases FSH and sperm production

Question 13

Update on male hormonal contraception

Answer 13

Question 14

Update on male hormonal contraception

Giulia Gava and Maria Cristina Meriggiola Ther Adv Endocrinol Metab 2019, Vol. 10: 1–9

• … testosterone a week is an option (TE)
• Or long lasting testosterone (…)
• Or depot with TU and … combined

Answer 14

• 200mg testosterone a week is an option (TE)
• Or long lasting testosterone (TU)
• Or depot with TU and NETE combined

Question 15

Side Effects of Male Hormonal Contraceptives

• Testosterone-only regimens: a…, altered …, night …, … weight, and … changes.
• The combination of testosterone with a … allowed a reduction of testosterone dose minimizing … side effects.
  
  • Progestins derived from …, which retain their androgenic activity, more often caused androgen-related adverse side effects such as …, … or decreased … …
• Interestingly, adverse side events reported by 93% of men on active treatment were also reported by 81% of men on placebo treatment.

Answer 15

• Testosterone-only regimens: acne, altered libido, night sweats, increased weight, and mood changes.
• The combination of testosterone with a progestin allowed a reduction of testosterone dose minimizing androgenic side effects.
  
  • Progestins derived from nortestosterone, which retain their androgenic activity, more often caused androgen-related adverse side effects such as weight gain, acne, or decreased HDL- cholesterol.
• Interestingly, adverse side events reported by 93% of men on active treatment were also reported by 81% of men on placebo treatment.